Human Molecular Genetics, 2002, Vol. 11, No. 15 1687-1696
© 2002 Oxford University Press
PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway
1Clinical Cancer Genetics Program, 2Human Cancer Genetics Program, 3Division of Human Genetics, Department of Internal Medicine, 4Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, 5Department of Molecular Genetics and 6Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA and 7CRC Human Cancer Genetics Research Group, University of Cambridge, UK
Received February 11, 2002; Accepted May 21, 2002
The tumor suppressor PTEN possesses lipid and protein phosphatase activities. It has been well established that the lipid phosphatase activity is essential for its tumor-suppressive function via the phosphoinositide 3-kinase (PI3K) and Akt pathways. The precise role of the protein phosphatase activity is still unclear. In the current study, we demonstrate that overexpression of wild-type PTEN in the MCF-7 breast cancer line results in phosphatase activity-dependent decreases in the phosphorylation of ETS-2, which is a transcription factor whose DNA-binding ability is controlled by phosphorylation. Exposure of MCF-7 cells to insulin, insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF) can lead to the phosphorylation of ETS-2, Akt and ERK1/2. The MEK inhibitor PD590089 abrogates insulin-stimulated phosphorylation of ETS-2. In contrast, the PI3K inhibitor LY492002 has no effect on insulin-stimulated phosphorylation of ETS-2, despite the fact that it diminishes insulin-stimulated phosphorylation of Akt. Interestingly, overexpression of PTEN in MCF-7 leads to blockade of insulin-stimulated, but not EGF-stimulated, phosphorylation of ERK, accompanied by dramatic decreases in ETS-2 phosphorylation. We further show that the relationship of PTEN and ETS-2 has functional significance by demonstrating that PTEN abrogates activation of the uPA Ras-responsive enhancer, a target of ETS-2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. Our observations, therefore, suggest that PTEN blocks insulin-stimulated ETS-2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS-2 may be mediated through PTEN's protein phosphatase activity.
* To whom correspondence should be addressed at: The Ohio State University Human Cancer Genetics Program, 420 W. 12th Avenue, Suite 690 Tzagournis MRF, Columbus, OH 43210, USA. Tel: +1 6142922347; Fax: +1 6146883582; Email: eng-1{at}medctr.osu.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. M. Planchon, K. A. Waite, and C. Eng The nuclear affairs of PTEN J. Cell Sci., February 1, 2008; 121(3): 249 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Chung, M. C. Ostrowski, T. Romigh, T. Minaguchi, K. A. Waite, and C. Eng The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation Hum. Mol. Genet., September 1, 2006; 15(17): 2553 - 2559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhang, F. Li, A. Bulloj, Y.-w. Zhang, G. Tong, Z. Zhang, F.-F. Liao, and H. Xu Tumor-suppressor PTEN affects tau phosphorylation, aggregation, and binding to microtubules FASEB J, June 1, 2006; 20(8): 1272 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Chung and C. Eng Nuclear-Cytoplasmic Partitioning of Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Differentially Regulates the Cell Cycle and Apoptosis Cancer Res., September 15, 2005; 65(18): 8096 - 8100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Agrawal, R. Pilarski, and C. Eng Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN Hum. Mol. Genet., August 15, 2005; 14(16): 2459 - 2468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Waite, M. R. Sinden, and C. Eng Phytoestrogen exposure elevates PTEN levels Hum. Mol. Genet., June 1, 2005; 14(11): 1457 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Eason, M. C. Velarde, L. Chatman Jr, S. R. Till, Y. Geng, M. Ferguson, T. M. Badger, and R. C. M. Simmen Dietary Exposure to Whey Proteins Alters Rat Mammary Gland Proliferation, Apoptosis, and Gene Expression during Postnatal Development J. Nutr., December 1, 2004; 134(12): 3370 - 3377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Musatov, J. Roberts, A. I. Brooks, J. Pena, S. Betchen, D. W. Pfaff, and M. G. Kaplitt Inhibition of neuronal phenotype by PTEN in PC12 cells PNAS, March 9, 2004; 101(10): 3627 - 3631. [Abstract] [Full Text] [PDF]
|
|